This work was in part supported by a grant from the National Institute of Health (GM42798).
The invention relates to new taxanes possessing strong antitumor activities, precursors of these compounds, compositions including these compounds, and processes for synthesizing these compounds and methods for treating tumors by using these new compounds.
Taxol is currently considered the most exciting "lead" compound in cancer chemotherapy. Taxol is a complex diterpene isolated from the bark of Taxus Brevifolia (Pacific Yew). Taxol possesses high cytotoxicity and strong antitumor activity against different cancers which have not been effectively treated by existing antitumor drugs. For example, taxol has been approved by FDA in late 1992 for the treatment of advanced ovarian cancer, and is currently in phase II clinical trials for breast and lung cancers.
Although Taxol is an important "lead" compound in cancer chemotherapy, Taxol has limited solubility in aqueous media, resulting in serious limitations to its use. It is also common that better drugs can be derived from naturally occurring "lead" compounds. In fact, French researchers have discovered a new anticancer agent by modifying the C-13 side chain of Taxol. This unnatural compound, named "Taxotere", has t-butoxycarbonyl instead of benzoyl on the amino group of (2R,3S)-phenylisoserine moiety at the C-13 position and a hydroxyl group instead of acetoxy group at C-10. Taxotere has antitumor activity superior to Taxol with better bioavailability. Taxotere is currently in phase II clinical trials in the United States, Europe, and Japan.
Taxol and Taxotere have chemical structures as follows: ##STR3##
A recent report on clinical trials of Taxol and Taxotere has disclosed that Taxol has side effects such as nerve damage, muscle pain or disturbances in heart rhythm. Taxotere also has side effects. For example, Taxotere provokes mouth sores and a plunge in white blood cell count. There are other minor side effects for these two drugs.
Taxol's poor water solubility causes practical problems in its pharmaceutical applications. For example, pharmaceutical formulations containing Taxol may require special carriers. Maximum dosages in Taxol drugs are also limited by the solubility of Taxol.
Taxotere, on the other hand, has a somewhat improved water solubility and thus better pharmacological properties than Taxol, but this antitumor agent also has a solubility problem.
It has been found that 14-Hydroxy-10-deacetylbaccatin III (14-OH-DAB), ##STR4## has much higher water solubility than the usual 10-deacetylbaccatin III. 10-deacetylbaccatin III is currently used for production of Taxol and Taxotere. This higher solubility of 14-OH-DAB is due to an extra hydroxyl group at the C-14 position. Therefore, new antitumor taxanes derived from 14-OH-DAB are expected to have substantially improved water solubility and pharmacological properties as therapeutic agents. The improved pharmacological properties are believed to be related to modifications in toxicity and activity spectra against different types of cancer.
Accordingly, it is an object of the invention to develop new anti-tumor agents of the Taxol or Taxotere class which have distinct structural differences which enhance solubility.
It is a further object of the present invention to provide a series of new taxanes derived from 14-OH-DAB which possess strong antitumor activities with better therapeutic profile. It is yet another object of the present invention to synthesize the new taxanes in high yield with a minimum number of syntheses steps.